Functional implications of the TNF

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): For both adults and young children acute, and repetitive exposure of the airways to air toxins has had led to both transient, and reversible airway injury, but also to remodeling of the airway with impairment of lung growth and pulmonary function. In the completely normal/healthy airway, exposure to O3, a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophil infiltration, and bronchial hyperreactivity. Inhalation of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (TNF) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. We have recently found a link between these 2 challenges: whereby in single laboratory exposures of young healthy subjects (n=135), a common single nucleotide polymorphism (SNP) in the TNF gene (-308), confers susceptibility to an ambient concentration of O3. Our preliminary results were highly significant and subjects, homozygotic (A/A) or heterozygotic (G/A) for the mutant allele of the TNFa (-308) polymorphism, were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type TNFa (-308) (G/G) haplotype. Previous reports suggest that the TNFa (-308) polymorphism leads to increased TNF gene transcription and increased TNFa cytokine production. However, the functional significance of this common TNF polymorphism remains controversial;and moreover, the functional implications of the TNFa (-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects - homozygotic (AA) or heterozygotic (GA) for the mutant allele of the TNFa (-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pro-inflammatory cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR. The proposed research is focused on understanding the interaction between host factors and exposure to a prototypal urban air pollutant. Results from the research plan will help understand the functional contribution of a common polymorphism of TNFa to the initiation inflammatory airway disease, and assign and validate genetic factors that confer vulnerability to O3. PUBLIC HEALTH RELEVANCE. The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects that occur during and following exposure to respirable airborne irritants.